We describe here preliminary data demonstrating thatCIB, a molecule we previously identified in a yeast-two hybrid screen as binding to the alphaIIb cytoplasmic domain, also binds to and activates p21-activated kinase or PAK1, with activation of this serine/threonine kinase occurring both in vitro and in vivo. Moreover, we provide evidence demonstrating that CIB plays a critical role in regulating fundamental cytoskeletal structure, cell shape, and cell spreading, which likely involve both CIB/PAK and other CIB-regulated mechanisms. Thus, CIB is emerging as a regulatory molecule of crucial importance to mtfltiple adhesive- and cytoskeletal-related functions. The interaction of CIB with PAK1 has also prompted us to consider the potential role of PAK1 in platelet function. While PAK represents a significant topic in the cancer field due to its effects on cytoskeletal assembly and cell motility, its role in platelets has not been addressed. Here we also provide preliminary data from PAK-/- murine platelets for a significant role of PAK in alphaIIb-beta3 activation. We propose to expand upon our observations with the following specific aims, first to determine the effects of overexpressed, knocked-down and knocked-out CIB on integrin activation and platelet thrombotic function in megakaryocytes and platelets in multiple in vitro, ex vivo and in vivo systems, second, to characterize the structural basis for the interaction of CIB with PAK1 and the alphaIIb integrin cytoplasmic domain, third, to define the CIB/PAK signaling complex in platelets, and finally to characterize the function of PAK1-/- murine platelets and megakaryocytes ex vivo and in vivo. These studies will not only provide novel information on potential therapeutic targets in platelets but will reveal fundamental roles of CIB and Pak1 in the regulation of cellular function.